Ruxolitinib phosphate

Ruxolitinib, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile phosphate, has a molecular weight of 404.36 kDa. Ruxolitinib is soluble in aqueous solutions at pH 1-8. Ruxolitinib tablets are stable at 20-25°C and tolerate brief exposures to temperatures outside this range, if they stay within 15-30°C.

Ruxolitinib is an oral inhibitor of JAK1 and JAK2, which is approved for the treatment of myeloproliferative neoplasm-associated myelofibrosis, further myeloproliferative neoplasms, polycythemia vera and refractory cancer. In the USA, Canada and EU, ruxolitinib is approved for the treatment of patients with intermediate or high-risk PMF, post-PV MF or post-ET MF. In addition, ruxolitinib recently has been approved for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea, based on the results of Phase II and III clinical studies. To date, ruxolitinib has been approved for indications in MF in 83 countries.

Common side effects of ruxolitinib treatment include anaemia and thrombocytopenia. The decline of circulating erythrocytes following ruxolitinib treatment could result in part from stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface. Cellular mechanisms involved in the execution of eryptosis include oxidative stress, Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), ceramide, decline of cytosolic ATP, caspases, stimulated activity of casein kinase 1α, Janus-activated kinase JAK3, protein kinase C, and p38 kinase, as well as impaired activity of AMP activated kinase AMPK, cGMP-dependent protein kinase, PAK2 kinase and sorafenib/sunitinib sensitive kinases.

The phosphate salt of Ruxolitinib (R702000). Ruxolitinib is a selective Janus tyrosine kinase (JAK1 and JAK2) inhibitor used in the treatment of myeloproliferative neoplasms and psoriasis.

ChEBI: A phosphate salt obtained by reaction ruxolitinib with one equivalent of phosphoric acid. Used for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essent al thrombocythemia myelofibrosis.

Ruxolitinib phosphate is a potent, selective, ATP competitive inhibitor of tyrosine-protein kinases JAK1 and JAK2 which acts by attenuating cytokine signaling and promotes apoptosis. Ruxolitinib was discovered and developed by Incyte, is marketed under the brand name Jakafi,and is approved for the treatment of patients with myelofibrosis (MF), including primary MF, post-polycythemia vera MP, and post-essential thrombocythemia MF. Ruxolitinib is also undergoing clinical evaluation against a wide variety of cancer indications including metastatic prostate cancer, pancreatic cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, and breast cancer. Additionally, ruxolitinib is being evaluated for the treatment of psoriasis and thrombocytopenia.

Ruxolitinib contains one chiral center, and three general strategies for its preparation have been reported.165¨C167 These include a racemic synthesis followed by chiral separation or resolution, introduction of the side chain via an aza-Michael addition of the pyrazole fragment to 3- cyclopentylpropiolonitrile and asymmetric hydrogenation of the resulting alkene, and through introduction of the side chain via an organocatalytic, asymmetric aza-Michael addition. The route described herein utilizes the first strategy as this appears to be the largest scale reported.
The synthesis was initiated by SEM protection of commercially available chloropyrrolopyrimidine 201 to provide the protected chloropyrrolopyrimidine 202 in 89% yield. Suzuki coupling of 202 with the pyrazole pinacolatoboronate 203 gave pyrazole 204 in 64% yield. aza-Michael reaction of pyrazole 204 with 3-cyclopentylacrylonitrile 205 was accomplished in the presence of DBU to furnish SEM-protected ruxolitinib 206 in 98% yield as the racemate. The desired enantiomer 207 was isolated via chiral column separation in 93.5% yield and 99.4% ee, on 100 kg scale. Removal of the SEM group was accomplished through a two step process via treatment with lithium tetrafluoroborate and aqueous ammonium hydroxide, ultimately giving rise to ruxolitinib 208 in 84% yield. The phosphate salt was then prepared by treatment with phosphoric acid. Crystallization from MeOH/i-PrOH/n-heptane gave ruxolitinib phosphate (XX) in good overall yield in 99.8% ee. Pyrazole pinacolatoboronate 203 was prepared from pyrazole 209 via iodination with N-iodosuccinimide followed by reaction with trimethyl silyl chloride to give protected iodopyrazaole 210 in high yield. Reaction of 210 with i-PrMgCl to form the corresponding Grignard reagent followed by reaction with isopropylpinacolborane 211 provided Suzuki boronate synthon 203 in 55% yield.

Store at -20°C